This invention relates to processes for modifying or substituting groups on azetidines, particularly replacing N-tertiary butyl groups with more easily removed groups. The azetidine ring was first identified in 1888 but has not received much interest because of the difficulties in preparing the compounds and the poor yields associated with the various preparative methods. There are important areas of chemistry and biochemistry arising from the azetidinyl structure which are not researched because the compounds can not be synthesized. Aziridines have biological activity. L-azetidine-2-carboxylic acid is an amino acid that can replace 1-proline in protein synthesizing systems. Polyoximic acid includes an azetidinyl ring and this acid is a constituent of an antibiotic nucleoside tripeptide, polyoxin A.
The aza substituted, 3-substituted azetidines are especially difficult to prepare. The most available member is the N-tertiary butyl,3-hydroxyazetidine. The next most available other member is N-benzhydryl,3-hydroxyazetidine. Other than these members, attempts to prepare the amines, amides, sulfinamides, and others lead to linear polymers, eight member rings, etc. There is a powerful tendency for the four member ring to open and thus the azetidinyl structure is not preserved. When the 3-substituent is to be modified from the hydroxyl group, it generally is converted via mesylate or chloride intermediates. In order to convert the aza group it is usual to proceed by a benzhydryl group as the aza substituent and then replace it with the corresponding hydrogen to the secondary amine. This is then modified to the corresponding target group such as alkyl, acetyl, sulfonyl, haloalkyl, nitrogen, etc. It is very desirable to provide processes which will make substituted aza azetidines with a wide variety of substituents and under mild conditions.